EP0480641B1 - Tricyclische Heteroringe - Google Patents

Tricyclische Heteroringe Download PDF

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EP0480641B1
EP0480641B1 EP91309118A EP91309118A EP0480641B1 EP 0480641 B1 EP0480641 B1 EP 0480641B1 EP 91309118 A EP91309118 A EP 91309118A EP 91309118 A EP91309118 A EP 91309118A EP 0480641 B1 EP0480641 B1 EP 0480641B1
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formula
compound
chloro
carboxy
group
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EP0480641A1 (de
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Howard Tucker
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Syngenta Ltd
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Zeneca Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D267/20—[b, f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16—[b, f]-condensed

Definitions

  • This invention relates to novel tricyclic heterocycles, or pharmaceutically-acceptable salts thereof, which possess useful pharmacological properties. More particularly the compounds of the invention may be used to counteract mild or moderate pain by virtue of their anti-hyperalgesic properties.
  • the invention also relates to processes for the manufacture of said tricyclic heterocycles, or pharmaceutically-acceptable salts thereof; to novel pharmaceutical compositions containing them; and to the use of said compounds in the production of an anti-hyperalgesic effect in the human or animal body.
  • the compounds of the invention may be used to counteract mild to moderate pain such as the pain associated with inflammatory conditions (such as rheumatoid arthritis and osteoarthritis), postoperative pain, post-partum pain, the pain associated with dental conditions (such as dental caries and gingivitis), the pain associated with burns (such as sunburn) and the pain associated with sports injuries and sprains.
  • a hyperalgesic state is present, i.e. a condition in which a warm-blooded animal is extremely sensitive to mechanical or chemical stimulation which would normally be painless.
  • a hyperalgesic state is known to accompany certain physical injuries to the body, for example the injury inevitably caused by surgery.
  • Hyperalgesia is also known to accompany certain inflammatory conditions in man such as arthritic and rheumatic disease. It is known that low doses of prostaglandin E1 or prostaglandin E2 (hereinafter PGE1 and PGE2 respectively) can induce the hyperalgesic state. Thus, for example, a long-lasting hyperalgesia occurs when PGE1 is infused in man and, in particular, the co-administration of PGE1 with a further chemical stimulant such as bradykinin causes marked pain. Thus it is believed that prostaglandins such as PGE1 and PGE2 act to sensitise pain receptors to mechanical or chemical stimulation.
  • PGE2 An alternative way of ameliorating the effects of PGE2 is to use an agent capable of antagonising its sensitising effects at the receptor or receptors responsible for mediating hyperalgesia. Certain compounds which possess such prostaglandin-antagonist properties are known. Thus it is known that various 10,11-dihydrodibenzo[b,f][1,4]oxazepine-10-carboxylic acid hydrazides are PGE2 antagonists and these are stated to possess analgesic properties [European Patent Application No. 0218077].
  • the compounds of the invention also possess anti-inflammatory, anti-pyretic and anti-diarrhoeal properties by virtue of antagonism of the effects of PGE2.
  • a tricyclic heterocycle of the formula I (set out hereinafter) wherein X is oxy, thio, sulphinyl, sulphonyl, amino, (1-4C)alkylamino or methylene, the last named group optionally bearing one or two (1-4C)alkyl groups; Y is carbonyl or methylene, the latter group optionally bearing one or two (1-4C)alkyl groups; each R1, which may be the same or different, is selected from hydrogen, halogeno, trifluoromethyl, nitro, cyano, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (1-4C)alkylamino and di-(1-4C)alkylamino; m and n, which may be the same or different, is the integer 1 or 2; A1 is a direct
  • alkyl includes both straight-chain and branched-chain alkyl groups.
  • references to individual alkyl groups such as “propyl” are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only.
  • An analogous convention applies to other generic terms.
  • the invention includes in its definition of active ingredient any such optically active or racemic form which possesses anti-hyperalgesic properties.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • anti-hyperalgesic properties may be evaluated using the standard laboratory techniques referred to hereinafter.
  • a suitable value for the (1-4C)alkyl group when X is (1-4C)alkylamino, or X or Y is methylene which bears one or two (1-4C)alkyl groups is, for example, methyl, ethyl, propyl or isopropyl.
  • each R1 which may be the same or different, when it is halogeno is, for example, fluoro, chloro or bromo; when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl or tert -butyl; when it is (1-4C)alkoxy is, for example, methoxy, ethoxy, propoxy or isopropoxy; when it is (1-4C)alkylthio is, for example, methylthio, ethylthio, propylthio or isopropylthio; when it is (1-4C)alkylsulphinyl is, for example, methylsulphinyl, ethylsulphinyl, propylsulphinyl or isopropylsulphinyl; when it is (1-4C)alkylsulphonyl is, for example, methyl
  • a suitable value for A1 when it is (1-6C)alkylene is, for example, methylene, ethylene, ethylidene, trimethylene, propylidene, propylene, tetramethylene or pentamethylene; when it is (3-6C)alkenylene is, for example, 2-propenylene, 2-methylprop-2-enylene, 2-butenylene or 3-butenylene; and when it is (3-6C)alkynylene is, for example, 2-propynylene, 2-methylprop-2-ynylene, 2-butynylene or 3-butynylene.
  • a suitable value for Ar when it is phenylene is, for example, 1,2-phenylene, 1,3-phenylene or 1,4-phenylene.
  • a suitable value for the one or two substituents which may be present on Ar when it is halogeno is, for example, fluoro, chloro or bromo; when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl or tert -butyl; when it is (1-4C)alkoxy is, for example, methoxy, ethoxy, propoxy or isopropoxy; when it is (1-4C)alkylthio is, for example, methylthio, ethylthio, propylthio or isopropylthio; when it is (1-4C)alkylsulphinyl is, for example, methylsulphinyl, ethylsulphinyl, propylsulphinyl or isopropylsulphinyl; when it is (1-4C)alkylsulphonyl is, for example
  • a suitable value for R2 when G is a group of the formula: -CONH-SO2R2 and R2 is (1-4C)alkyl is, for example, methyl, ethyl, propyl or isopropyl.
  • G is a group of the formula: -CONH-SO2R2 and R2 is benzyl or phenyl which may optionally bear one or two substituents
  • a suitable value for said substituent when it is halogeno is, for example, fluoro, chloro or bromo
  • when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl or isopropyl
  • when it is (1-4C)alkoxy is, for example, methoxy, ethoxy, propoxy or isopropoxy.
  • a suitable value for an in-vivo hydrolysable ester of a tricyclic heterocycle of the formula I wherein G is carboxy is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid, for example, an ester formed with a (1-6C)alcohol such as methanol, ethanol, ethylene glycol, propanol or butanol, or with a phenol or benzyl alcohol such as phenol or benzyl alcohol or a substituted phenol or benzyl alcohol wherein the substituent is, for example, a halogeno (such as fluoro or chloro), (1-4C)alkyl (such as methyl) or (1-4C)alkoxy (such as methoxy) group.
  • a halogeno such as fluoro or chloro
  • (1-4C)alkyl such as methyl
  • (1-4C)alkoxy such as methoxy
  • a suitable value for an amide of a tricyclic heterocycle of the formula I wherein G is carboxy is, for example, a N-(1-6C)alkyl or N,N-di-(1-6C)alkyl amide such as a N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.
  • a suitable pharmaceutically-acceptable salt of a tricyclic heterocycle of the invention is, for example, an acid-addition salt of a tricyclic heterocycle of the invention which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a tricyclic heterocycle of the invention which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an acid-addition salt of a tricyclic heterocycle of the invention which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluor
  • novel compounds of the invention include, for example, tricyclic heterocycles of the formula I wherein:-
  • a preferred compound of the invention comprises a tricyclic heterocycle of the formula I wherein X is oxy, thio, amino, methylamino, ethylamino or methylene; Y is methylene optionally bearing one or two methyl or ethyl groups; each R1, which may be the same or different, is selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methyl, ethyl, methoxy, ethoxy, methylthio, methylsulphinyl and methylsulphonyl; each of m and n is the integer 1; A1 is methylene, ethylene, ethylidene, trimethylene, propylidene, propylene, 2-propenylene or 2-propynylene; A2 is a direct link to G; Ar is 1,2-phenylene, 1,3-phenylene or 1,4-phenylene which may optionally bear one substituent selected from fluoro, chloro
  • a preferred compound of the invention comprises a tricyclic heterocycle of the formula I wherein X is oxy; Y is methylene optionally bearing one or two methyl or ethyl groups; each R1, which may be the same or different, is selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro and cyano; each of m and n is the integer 1; A1 is methylene, ethylene, ethylidene, trimethylene, propylidene or propylene; A2 is a direct link to G; Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear one substituent selected from fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy; and G is carboxy or an in-vivo hydrolysable ester thereof; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises a tricyclic heterocycle of the formula I wherein X is oxy, thio, amino or methylene; Y is methylene; each R1, which may be the same or different, is selected from hydrogen, chloro and trifluoromethyl; each of m and n is the integer 1; A1 is methylene, trimethylene or 2-propenylene; A2 is a direct link to G; Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear one substituent selected from fluoro, nitro, hydroxy, amino and methoxy; and G is carboxy or an in-vivo hydrolysable ester thereof; or G is a group of the formula:- -CONHSO2R2 wherein R2 is phenyl; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises a tricyclic heterocycle of the formula I wherein X is oxy; Y is methylene; each R1, which may be the same or different, is selected from hydrogen, chloro and trifluoromethyl; each of m and n is the integer 1; A1 is methylene or trimethylene; A2 is a direct link to G; Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear one substituent selected from fluoro, nitro, hydroxy, amino and methoxy; and G is carboxy or an in-vivo hydrolysable ester thereof; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises a tricyclic heterocycle of the formula I wherein X is oxy; Y is methylene; each R1, which may be the same or different, is selected from hydrogen, fluoro, chloro and trifluoromethyl; each of m and n is the integer 1: A1 is methylene; A2 is a direct link to G; Ar is 1,3-phenylene or 1,4-phenylene; and G is carboxy or an in-vivo hydrolysable ester thereof; or a pharmaceutically-acceptable salt thereof.
  • a specific preferred compound of the invention is, for example, the following tricyclic heterocycle of the formula I, or an in-vivo hydrolysable ester thereof or a pharmaceutically-acceptable salt thereof:- 3-(8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-ylmethyl)benzoic acid, 4-(8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-ylmethyl)benzoic acid, 4-[3-(8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-yl)propyl]benzoic acid, 4-(8-trifluoromethyl-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-ylmethyl)benzoic acid or 5-(8-chloro-10,11-dihydrodibenzo[b
  • a compound of the invention comprising a tricyclic heterocycle of the formula I, or when G is carboxy an in-vivo hydrolysable ester or an amide thereof, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of structurally-related compounds. Such procedures are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, X, Y, R1, m, n, A1, A2, Ar and G have any of the meanings defined hereinbefore.
  • an in-vivo hydrolysable ester of a compound of the formula I wherein G is carboxy When an in-vivo hydrolysable ester of a compound of the formula I wherein G is carboxy is required, it may be obtained, for example, by reaction of said compound of the formula I wherein G is carboxy, or a reactive derivative thereof as defined hereinbefore, with a suitable esterifying reagent using a conventional procedure.
  • a pharmaceutically-acceptable salt of a compound of the formula I When a pharmaceutically-acceptable salt of a compound of the formula I is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure.
  • a tricyclic heterocycle of the formula I possesses anti-hyperalgesic properties and hence is of value in the treatment of the hyperalgesic state which, for example, accompanies inflammatory conditions such as rheumatoid arthritis and osteoarthritis.
  • the compound 4-(8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-ylmethyl)benzoic acid has a pA2 value of 7.0 in Test (a) and an ED50 of 19 mg/kg in Test (b) on oral dosing; and the compound 3-(8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-ylmethyl)benzoic acid has a pA2 of 7.4 in Test (a) and it possesses significant activity at 100 mg/kg in Test (c) on oral dosing.
  • Prostanoid receptors and in particular receptors for PGE2 have been tentatively characterised by Kennedy et al . (Advances in Prostaglandin, Thromboxane and Leukotriene Research, 1983, 11 , 327).
  • the known PGE2 anatagonist SC-19220 blocks the effect of PGE2 on some tissues such as guinea pig ileum or dog fundus but not on other tissues such as the cat trachea or chick ileum. Those tissues which did possess SC-19220 affected PGE2 receptors were said to possess EP1 receptors. Accordingly compounds of the present invention, possessing activity in Test (a), are EP1 antagonists.
  • a pharmaceutical composition which comprises a tricyclic heterocycle of the formula I, or when G is carboxy an in-vivo hydrolysable ester thereof or an amide thereof, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
  • the composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension.
  • the above compositions may be prepared in a conventional manner using conventional excipients.
  • the amount of active ingredient (that is a tricyclic heterocycle of the formula I or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • a tricyclic heterocycle of the formula I or when G is carboxy an in-vivo hydrolysable ester thereof or an amide thereof, or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.
  • a tricyclic heterocycle of the formula I or when G is carboxy an in-vivo hydrolysable ester thereof or an amide thereof, or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for use in the production of an anti-hyperalgesic effect in the human or animal body.
  • a method for producing an anti-hyperalgesic effect in the human or animal body in need of such treatment which comprises administering to said body an effective amount of a tricyclic heterocycle of the formula I, or when G is carboxy an in-vivo hydrolysable ester thereof or an amide thereof, or a pharmaceutically-acceptable salt thereof.
  • a tricyclic heterocycle of the formula I is useful in treating the hyperalgesic state which, for example, accompanies inflammatory conditions such as rheumatoid arthritis and osteoarthritis.
  • a daily dose in the range for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses.
  • lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, 0.5 mg to 30 mg per kg body weight will generally be used.
  • a dose in the range for example, 0.5 mg to 25 mg per kg body weight will be used.
  • the compounds of the formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to antagonise the effects of PGE2. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of the formula I are of value in the treatment of certain inflammatory diseases which are currently treated with a cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug (NSAID) such as indomethacin, acetylsalicyclic acid, ibuprofen, sulindac, tolmetin and piroxicam.
  • NSAID cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug
  • Co-administration of a compound of the formula I with a NSAID can result in a reduction of the quantity of the latter agent needed to produce a therapeutic effect. Thereby the likelihood of adverse side-effects from the NSAID such as gastrointestinal effects are reduced.
  • a pharmaceutical composition which comprises a tricyclic heterocycle of the formula I, or when G is carboxy an in-vivo hydrolysable ester thereof or an amide thereof, or a pharmaceutically-acceptable salt thereof, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent, and a pharmaceutically-acceptable diluent or carrier.
  • compositions of the invention may in addition contain one or more therapeutic or prophylactic agents known to be of value for the treatment of mild or moderate pain.
  • a known mild opiate pain-killer such as dextropropoxyphene or codeine
  • an inhibitor of the enzyme 5-lipoxygenase such as those disclosed in European Patent Applications Nos. 0351194, 0375368, 0375404, 0375452, 037547, 0381375, 0385662, 0385663, 0385679, 0385680
  • 5-lipoxygenase such as those disclosed in European Patent Applications Nos. 0351194, 0375368, 0375404, 0375452, 037547, 0381375, 0385662, 0385663, 0385679, 0385680
  • Example 2 The procedures described in Example 1 were repeated except that 4-methoxycarbonylbenzyl bromide was used in place of 3-methoxycarbonylbenzyl bromide. There was thus obtained 4-(8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-ylmethyl)benzoic acid in 20% yield, m.p. 185°C.
  • Example 5 Using a similar procedure to that described in Example 4 except that the appropriate acetoxybenzyl bromide was used in place of 2-acetoxy-3-methoxycarbonylbenzyl bromide, and, where appropriate, a similar procedure to that described in Example 5, there were obtained the compounds described in Table II, the structures of which were confirmed by proton magnetic resonance and mass spectroscopy and by microanalysis.
  • the methyl 4-[3-(8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-yl)prop-1-ynyl]benzoate used as a starting material was obtained as follows:- A solution of 8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepine (0.463 g) in DMF (10 ml) was added dropwise to a stirred suspension of sodium hydride (60% w/w dispersion in vegetable oil, 0.08 g) in DMF (10 ml) which had been cooled to 0°C. The mixture was stirred at 0°C for 30 minutes.
  • Example 2 The procedures described in Example 1 were repeated except that 8-chloro-11-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazepine was used in place of 8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepine. There was thus obtained 3-(8-chloro-11-methyl-10,11-dihydrobenzo[b,f][1,4]oxazepin-10-ylmethyl)benzoic acid in 33% yield, m.p. 99°C.
  • the starting material 8-chloro-11-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazepine used as a starting material was obtained from 5'-chloro-2'-phenoxyacetanilide using analogous procedures to those described in Coll. Czech. Chem. Comm. , 1965, 30 , 463.
  • Example 2 The procedures defined in Example 2 were repeated except that 8-chloro-11-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazepine was used in place of 8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepine. There was thus obtained 4-(8-chloro-11-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-ylmethyl)benzoic acid in 27% yield, m.p. 148°C.
  • Example 2 The procedures described in Example 1 were repeated except that 8-chloro-10,11-dihydrodibenzo[b,f][1,4]thiazepine ( Coll. Czech. Chem. Comm. , 1959, 24 , 207) was used in place of 8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepine. There was thus obtained 3-(8-chloro-10,11-dihydrodibenzo[b,f][1,4]thiazepin-10-ylmethyl)benzoic acid in 2% yield, m.p. 193-194°C.
  • Example 2 The procedures defined in Example 2 were repeated except that 8-chloro-8,11-dihydrodibenzo[b,f][1,4]thiazepine was used in place 8-chloro-10,11-dihydrodibenzo[b,f][1,4]oxazepine. There was thus obtained 4-(8-chloro-10,11-dihydrodibenzo[b,f][1,4]thiazepin-10-ylmethyl)benzoic acid in 19% yield, m.p. 191-192°C.
  • aqueous layer was basified by the addition of 2N aqueous sodium hydroxide solution and extracted with ethyl acetate (25 ml). The organic extracts were combined, washed with a saturated aqueous sodium bicarbonate solution and with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 19:1 v/v mixture of methylene chloride and ethyl acetate as eluent. There was thus obtained methyl 4-(10,11-dihydro-5 H -dibenzo[b,e][1,4]diazepin-10-ylmethyl)benzoate (0.62 g) as an oil.
  • Example 20 The procedures described in Example 20 were repeated except that methyl 3-(11-oxo-10,11-dihydro-5 H -dibenzo[b,e][1,4]diazepin-10-ylmethyl)benzoate was used as the starting material. There was thus obtained 3-(10,11-dihydro-5 H -dibenzo[b,e][1,4]diazepin-10-ylmethyl)benzoic acid in 11% yield, m.p. 125-126°C.
  • the 5-ethyl-10,11-dihydro-5 H -dibenzo[b,e][1,4]diazepine used as a starting material was obtained as follows:- Acetic anhydride (4.1 g) was added dropwise to a stirred solution of 10,11-dihydro-5 H -dibenzo[b,e][1,4]diazepin-11-one (9.1 g) in pyridine (50 ml) and the mixture was heated to 100°C for 7 hours. The mixture was evaporated and the residue was purified by column chromatography using a 7:3 v/v mixture of methylene chloride and ethyl acetate as eluent. There was thus obtained 5-acetyl-10,11-dihydro-5 H -dibenzo[b,e][1,4]diazepin-11-one (2.8 g).
  • the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
  • the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
  • the aerosol formulations (h)-(k) may be used in conjunction with standard, metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

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Claims (9)

  1. Verfahren zur Herstellung eines tricyclischen Heterocyclus mit der folgenden Formel I:
    Figure imgb0023
     in der X für Oxy, Thio, Sulfinyl, Sulfonyl, Amino, (1-4C)Alkylamino oder Methylen steht, wobei die zuletzt genannte Gruppe gegebenenfalls eine oder zwei (1-4C)Alkyl-Gruppen trägt;
    Y für Carbonyl oder Methylen steht, wobei die letztere Gruppe gegebenenfalls eine oder zwei (1-4C)Alkyl-Gruppen trägt;
    jedes R¹, das gleich oder unterschiedlich sein kann, aus Wasserstoff, Halogen, Trifluormethyl, Nitro, Cyano, Hydroxy, Amino, (1-4C)Alkyl, (1-4C)Alkoxy, (1-4C)Alkylthio, (1-4C)Alkylsulfinyl, (1-4C)Alkylsulfonyl, (1-4C)Alkylamino und Di-(1-4C)alkylamino ausgewählt ist;
    m und n, die gleich oder unterschiedlich sein können, für die ganze Zahl 1 oder 2 stehen;
    A¹ für eine Direktbindung zu Ar steht, oder in der A¹ für (1-6C)Alkylen, (3-6C)Alkenylen oder (3-6C)Alkinylen steht;
    A² für eine Direktbindung zu G steht;
    Ar für Phenylen steht, das gegebenenfalls einen oder zwei Substituenten tragen kann, die aus Halogen, Trifluormethyl, Nitro, Cyano, Hydroxy, Amino, (1-4C)Alkyl, (1-4C)Alkoxy, (1-4C)Alkylthio, (1-4C)Alkylsulfinyl, (1-4C)Alkylsulfonyl, (1-4C)Alkylamino und Di-(1-4C)Alkylamino ausgewählt sind; und G für Carboxy, 1H-Tetrazol-5-yl oder für eine Gruppe mit der folgenden Formel steht:-



            -CONH-SO₂R²



    in der R² für (1-4C)Alkyl, Benzyl oder Phenyl steht, wobei die letzteren beiden gegebenenfalls einen oder zwei Substituenten tragen können, die aus Halogen, Trifluormethyl, Nitro, Cyano, Hydroxy, (1-4C)Alkyl und (1-4C)Alkoxy ausgewählt sind;
    oder, wenn G für Carboxy steht, eines in vivo hydrolysierbaren Esters davon oder eines Amids davon; oder eines pharmazeutisch geeigneten Salzes davon; dadurch gekennzeichnet, daß
    (a) eine Verbindung mit der folgenden Formel II:
    Figure imgb0024
     mit einer Verbindung mit der folgenden Formel:-



            Z-A¹-Ar-A²-G



    in der Z für eine austauschbare Gruppe steht, gekuppelt wird, mit der Maßgabe, daß jede Hydroxy-, Amino-, Alkylamino- oder Carboxy-Gruppe in diesen Reaktanten mit einer üblichen Schutzgruppe geschützt sein kann, oder alternativ keine derartige Gruppe geschützt werden muß, wonach jeder derartige Schutzgruppe mit üblichen Mitteln entfernt wird;
    (b) zur Herstellung einer Verbindung mit der Formel I, in der R¹ für (1-4C)Alkylthio steht, oder in der Ar einen (1-4C)Alkylthio-Substituenten trägt, eine Verbindung mit der Formel I, in der R¹ für einen austauschbaren Substituenten Z steht, oder in der Ar einen austauschbaren Substituenten Z trägt, einer Austauschreaktion mit einem (1-4C)Alkylthiol unterzogen wird;
    (c) zur Herstellung einer Verbindung mit der Formel I, in der R¹ für (1-4C)Alkylsulfinyl oder (1-4C)Alkylsulfonyl steht, oder in der Ar einen (1-4C)Alkylsulfinyl- oder (1-4C)Alkylsulfonyl-Substituenten trägt, eine Verbindung mit der Formel I, in der R¹ für (1-4C)Alkylthio steht, oder in der Ar einen (1-4C)Alkylthio-Substituenten trägt, oxidiert wird;
    (d) zur Herstellung einer Verbindung mit der Formel I, in der G für 1H-Tetrazol-5-yl steht, ein Nitril mit der folgenden Formel III:
    Figure imgb0025
     mit einem Azid umgesetzt wird;
    (e) zur Herstellung einer Verbindung mit der Formel I, in der G für eine Gruppe mit der folgenden Formel:



            -CONH-SO₂R²



    steht, eine Verbindung mit der Formel I, in der G für Carboxy steht, oder ein reaktives Derivat davon, mit einem Sulfonamid mit der folgenden Formel:-



            H₂N-SO₂R²



    umgesetzt wird, mit der Maßgabe, daß jede Hydroxy-, Amino- oder Alkylamino-Gruppe in diesen Reaktanten mit einer üblichen Schutzgruppe geschützt sein kann, oder alternativ keine derartige Gruppe geschützt werden muß, wonach jede derartige Schutzgruppe mit üblichen Mitteln entfernt wird;
    (f) zur Herstellung einer Verbindung mit der Formel I, in der R¹ für (1-4C)Alkoxy steht, oder in der Ar einen (1-4C)Alkoxy-Substituenten trägt, eine Verbindung mit der Formel I, in der R¹ für Hydroxy steht, oder in der Ar einen Hydroxy-Substituenten trägt, alkyliert wird;
    (g) zur Herstellung einer Verbindung mit der Formel I, in der A¹ für (3-6C)Alkinylen steht, ein Alkin mit der folgenden Formel IV:
    Figure imgb0026
     in der p für eine ganze Zahl von 1 bis 4 steht, mit einer Verbindung mit der folgenden Formel V:
    Figure imgb0027
     in der Z für einen austauschbaren Substituenten steht, gekuppelt wird;
    (h) zur Herstellung einer Verbindung mit der Formel I, in der A¹ für (3-6C)Alkenylen oder (1-6C)Alkylen steht, die entsprechende Verbindung, in der A¹ für (3-6C)Alkinylen steht, reduziert wird;
    (i) zur Herstellung einer Verbindung mit der Formel I, in der R¹ für Amino steht, oder in der Ar einen Amino-Substituenten trägt, eine Verbindung mit der Formel I, in der R¹ für Nitro steht, oder in der Ar einen Nitro-Substituenten trägt, reduziert wird; oder
    (j) zur Herstellung einer Verbindung mit der Formel I, in der Y für Methylen steht, eine Verbindung mit der Formel I, in der Y für Carbonyl steht, reduziert wird; und
    wenn ein in vivo hydrolysierbarer Ester einer Verbindung mit der Formel I, in der G für Carboxy steht, benötigt wird, dieser durch Umsetzung der Verbindung mit der Formel I, in der G für Carboxy steht, oder eines reaktiven Derivates davon, unter Verwendung eines üblichen Verfahrens mit einem geeigneten Veresterungsmittel erhalten werden kann;
    wenn ein Amid einer Verbindung mit der Formel I, in der G für Carboxy steht, benötigt wird, dieses durch Umsetzung der Verbindung mit der Formel I, in der G für Carboxy steht, oder eines reaktiven Derivats davon, unter Verwendung eines üblichen Verfahrens mit einem geeigneten Amin erhalten werden kann;
    und wenn ein pharmazeutisch geeignetes Salz einer Verbindung mit der Formel I benötigt wird, dieses durch die Umsetzung der Verbindung unter Verwendung eines üblichen Verfahrens mit einer geeigneten Säure oder Base erhalten werden kann.
  2. Verfahren nach Anspruch 1 zur Herstellung eines tricyclischen Heterocyclus mit der Formel I, in der X für Oxy, Thio, Amino, Methylamino, Ethylamino oder Methylen steht;
    Y für Methylen steht, das gegebenenfalls eine oder zwei Methyl- oder Ethyl-Gruppen trägt;
    jedes R¹, das gleich oder unterschiedlich sein kann, aus Wasserstoff, Fluor, Chlor, Brom, Trifluormethyl, Nitro, Cyano, Methyl, Ethyl, Methoxy, Ethoxy, Methylthio, Methylsulfinyl und Methylsulfonyl ausgewählt ist;
    m und n jeweils für die ganze Zahl 1 stehen;
    A¹ für Methylen, Ethylen, Ethyliden, Trimethylen, Propyliden, Propylen, 2-Propenylen oder 2-Propinylen steht;
    A² für eine Direktbindung zu G steht;
    Ar für 1,2-Phenylen, 1,3-Phenylen oder 1,4-Phenylen steht, das gegebenenfalls einen Substituenten tragen kann, der aus Fluor, Chlor, Brom, Trifluormethyl, Nitro, Cyano, Hydroxy, Amino, Methyl, Ethyl, Methoxy und Ethoxy ausgewählt ist; und
    G für Carboxy, 1H-Tetrazol-5-yl oder für eine Gruppe mit der folgenden Formel steht:-



            -CONHSO₂R²



    in der R² für Methyl, Ethyl oder Phenyl steht, wobei die letzte Gruppe gegebenenfalls einen Substituenten trägt, der aus Fluor, Chlor, Trifluormethyl, Nitro, Cyano, Hydroxy, Methyl und Methoxy ausgewählt ist;
    oder, wenn G für Carboxy steht, eines in vivo hydrolysierbaren Esters davon;
    oder eines pharmazeutisch geeigneten Salzes davon.
  3. Verfahren nach Anspruch 1 zur Herstellung eines tricyclischen Heterocyclus mit der Formel I, in der X für Oxy steht;
    Y für Methylen steht, das gegebenenfalls eine oder zwei Methyl- oder Ethyl-Gruppen trägt;
    jedes R¹, das gleich oder unterschiedlich sein kann, aus Wasserstoff, Fluor, Chlor, Brom, Trifluormethyl, Nitro und Cyano ausgewählt ist;
    m und n jeweils für die ganze Zahl 1 stehen;
    A¹ für Methylen, Ethylen, Ethyliden, Trimethylen, Propyliden oder Propylen steht;
    A² für eine Direktbindung zu G steht;
    Ar für 1,3-Phenylen oder 1,4-Phenylen steht, das gegebenenfalls einen Substituenten tragen kann, der aus Fluor, Chlor, Brom, Trifluormethyl, Nitro, Cyano, Hydroxy, Methyl, Ethyl, Methoxy und Ethoxy ausgewählt ist; und
    G für Carboxy oder einen in vivo hydrolysierbaren Ester davon steht;
    oder eines pharmazeutisch geeigneten Salzes davon.
  4. Verfahren nach Anspruch 1 zur Herstellung eines tricyclischen Heterocyclus mit der Formel, in der X für Oxy, Thio, Amino oder Methylen steht;
    Y für Methylen steht;
    jedes R¹, das gleich oder unterschiedlich sein kann, aus Wasserstoff, Chlor und Trifluormethyl ausgewählt ist;
    m und n jeweils für die ganze Zahl 1 stehen;
    A¹ für Methylen, Trimethylen oder 2-Propenylen steht;
    A² für eine Direktbindung zu G steht;
    Ar für 1,3-Phenylen oder 1,4-Phenylen steht, das gegebenenfalls einen Substituenten tragen kann, der aus Fluor, Nitro, Hydroxy, Amino und Methoxy ausgewählt ist; und
    G für Carboxy oder einen in vivo hydrolysierbaren Ester davon steht; oder in der
    G für eine Gruppe mit der folgenden Formel steht:-



            -CONHSO₂R²



    in der R² für Phenyl steht;
    oder eines pharmazeutisch geeigneten Salzes davon.
  5. Verfahren nach Anspruch 1 zur Herstellung eines tricyclischen Heterocyclus mit der Formel I, in der
    X für Oxy steht;
    Y für Methylen steht;
    jedes R¹, das gleich oder unterschiedlich sein kann, aus Wasserstoff, Chlor und Trifluormethyl ausgewählt ist;
    m und n jeweils für die ganze Zahl 1 stehen;
    A¹ für Methylen oder Trimethylen steht;
    A² für eine Direktbindung zu G steht;
    Ar für 1,3-Phenylen oder 1,4-Phenylen steht, das gegebenenfalls einen Substituenten tragen kann, der aus Fluor, Nitro, Hydroxy, Amino und Methoxy ausgewählt ist; und
    G für Carboxy oder einen in vivo hydrolysierbaren Ester davon steht;
    oder eines pharmazeutisch geeigneten Salzes davon.
  6. Verfahren nach Anspruch 1 zur Herstellung eines tricyclischen Heterocyclus mit der Formel I, in der
    X für Oxy steht;
    Y für Methylen steht;
    jedes R¹, das gleich oder unterschiedlich sein kann, aus Wasserstoff, Fluor, Chlor und Trifluormethyl ausgewählt ist;
    m und n jeweils für die ganze Zahl 1 stehen;
    A¹ für Methylen steht;
    A² für eine Direktbindung zu G steht;
    Ar für 1,3-Phenylen oder 1,4-Phenylen steht; und
    G für Carboxy oder einen in vivo hydrolysierbaren Ester davon steht;
    oder eines pharmazeutisch geeigneten Salzes davon.
  7. Verfahren nach Anspruch 1 zur Herstellung eines tricyclischer Heterocyclus mit der Formel I, oder eines in vivo hydrolysierbaren Esters davon, oder eines pharmazeutisch geeigneten Salzes davon, der aus folgendem ausgewählt ist:
    3-(8-Chlor-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-ylmethyl)benzoesäure,
    4-(8-Chlor-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-ylmethyl)benzoesäure,
    4-[3-(8-Chlor-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-yl)propyl]benzoesäure,
    4-(8-Trifluormethyl-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-ylmethyl)benzoesäure und
    5-(8-Chlor-10,11-dihydrodibenzo[b,f][1,4]oxazepin-10-ylmethyl)-2-hydroxybenzoesäure.
  8. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung, bei dem ein tricyclischer Heterocyclus mit der Formel I, oder, wenn G für Carboxy steht, ein in vivo hydrolysierbarer Ester davon oder ein Amid davon, oder ein pharmazeutisch geeignetes Salzes davon, nach einem der Ansprüche 1 bis 7 und ein pharmazeutisch geeignetes Streckmittel oder Trägermittel gemischt werden.
  9. Verwendung eines tricyclischen Heterocyclus mit der Formel I, oder, wenn G für Carboxy steht, eines in vivo hydrolysierbaren Esters davon oder eines Amids davon, oder eines pharmazeutisch geeigneten Salzes davon, nach einem der Ansprüche 1 bis 7 zur Herstellung eines Arzneimittels zur Verwendung für die Erzeugung einer antihyperalgesischen Wirkung im menschlichen oder tierischen Körper.
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US4559336A (en) * 1985-02-25 1985-12-17 G.D. Searle & Co. 8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(sulfinyl- and sulfonyl-containing acyl)hydrazides
US4614617A (en) * 1985-02-25 1986-09-30 G. D. Searle & Co. Intermediates for 8-chlorodibenz[(b,f)][1,4]oxazepine-10(11H)-carboxylic acid, 2-(sulfinyl- and sulfonyl-containing acyl)hydrazides
US4704386A (en) * 1985-08-29 1987-11-03 G. D. Searle & Co. 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(phenylsulfinyl-, and phenylsulfonyl)alkanoyl]hydrazides

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CA2051830A1 (en) 1992-04-09
AU8376391A (en) 1992-04-09
US5189033A (en) 1993-02-23
FI914476A0 (fi) 1991-09-24
JPH04288064A (ja) 1992-10-13
IE913156A1 (en) 1992-04-08
ZA917153B (en) 1992-06-24
DE69108665T2 (de) 1995-08-17
FI914476A (fi) 1992-04-09
ATE120737T1 (de) 1995-04-15
AU645837B2 (en) 1994-01-27
CA2051830C (en) 2002-01-01
DE69108665D1 (de) 1995-05-11
GB9021813D0 (en) 1990-11-21
IL99475A0 (en) 1992-08-18
EP0480641A1 (de) 1992-04-15
PT99170A (pt) 1992-09-30

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